The human immune system is comprised of cells that have differentiated into specific types (such as red, B or T) and hematopoietic stem cells (HSCs) that are not fully differentiated. HSCs grow and are capable of producing more HSCs and differentiated cells to perform a specific function. HSC transplant therapy represents an increasingly important modality in treating and curing human disease. HSC transplantation involves the use of HSCs to replace and initiate the production of cells that are missing or damaged due to disease or injury. Today, HSC transplantation is commonly used non-controversial treatment for hematopoietic diseases. HSC transplant therapy is a medical procedure in which bone marrow or processed circulating blood (all of which contain HSCs) are infused into the patient’s circulatory system, where they home to the bone cavity. Once established, they begin to grow and produce healthy blood and immune cells. Cells for this procedure are obtained from a donor, though, in some cases, the patient’s own cells may be used. Despite successful use, several limitations remain, including unavailability of appropriate donors and individuals treated with chemotherapy are unable to use their own HSCs. Umbilical cord blood cells has emerged as an excellent source of HSCs for individuals who lack an appropriate donor or cannot utilize their own HSCs, but at present have limited utility because of low HSC numbers per transplant leading to delayed recovery. Growing HSCs outside the body is an attractive strategy to obtain increased numbers of HSCs for transplantation because successful HSC transplants have been correlated with HSC dose. Extensive research has been employed to identify the growth conditions to expand HSCs , but to date the critical factors remain unknown. Therefore, to identify compounds that promote HSC expansion we performed a high-throughput screening assay and identified small molecules that expand HSCs outside the body. HSCs grown with the most potent compound produced ten times more HSCs compared with control.
The goal of this proposal is to develop this compound for clinical applications. HSCs expanded with this compound may be used to: replace diseased bone marrow with healthy, functioning bone marrow for patients with blood diseases such as aplastic anemia; replace bone marrow damaged by high-dose chemotherapy or radiation therapy; used to treat patients with a variety of cancers such as leukemia and lymphoma; and provide genetically healthy and functioning bone marrow to treat patients with genetic diseases such as sickle cell anemia. To reach these goals we will assemble a team of scientists, hematologists and oncologists to plan the appropriate experiments leading to human trials. Because HSC are the only approved stem cell therapy and HSC transplants are routinely performed this project is achievable within the next five years, and these experiments may result in the first regenerative stem cell drug.
Small molecule controlled ex vivo HSC expansion will have a profound benefit on the treatment of many blood diseases. Ex vivo expanded HSCs may be used to accelerate the hematopoietic reconstitution and immune cell function during autologous or allogeneic transplantation for the treatment of patients with inherited immunodeficiency, autoimmune disease and diverse hematopoietic disorders. HSC transplantation is also used to restore the hematopoietic and immune system after myeloablative effects following high-dose chemotherapy or ionizing radiation therapy in cancer patients. In addition, ex-vivo HSC expansion will extend the utility of the Cord Blood registry by circumventing the low number of functional HSC available for transplant. For example, umbilical cord blood transplantation (UCBT) has become an established therapy for patients without matched related or unrelated donors. Compared to bone marrow transplants, UCB collection is easier and safer. It is also quicker to perform UCBT from the time of beginning of donor search. One of the major advantages is the naïve nature of the newborn’s immune system. This allows transplantations with less restriction of the HLA system, and with fewer graft versus host disease cases. Owing to a limited number of stem cells available in a typical UCB unit and therefore delayed engraftment when compared to marrow or mobilized peripheral blood, the prime focus for this therapy continues to be the pediatric patient. Nevertheless this form of transplant is emerging as a viable alternative in adults, provided there are sufficient cells in the UCB unit and the patient is a small to average-sized adult. Although UCBT permits the use of mismatched donors and are available more quickly than matched unrelated donor grafts, the main problems after the infusion of an UCB unit are delayed engraftment of neutrophils and platelets and aberrant immune reconstitution - both leading to a higher mortality.
In 2004, two large retrospective UCBT studies on adults transfused with a median of 2.3 x 107 total nucleated cells (TNC)/kg showed no difference in leukemia-free survival between the human leukocyte antigen (HLA)-mismatched cord blood group and the HLA-matched marrow groups using allele matching at HLA-DRB1 and serologic matching at HLA-A and -B. Based on these results, UCBT could become the treatment of choice if a HLA class I and class II (eight out of eight) matched unrelated adult donor is not available. Unfortunately 90% of adults referred for a UCBT are ineligible to receive an UCB graft based on their weight at the recommended cell dose and with no more than two HLA mismatches. Thus efforts to increase the number of HSC infused are paramount. Using a small molecule, like the one we identified, will allow for ex vivo expansion of UCB HSCs and make UCBT available to more patients, decrease engraftment times and allow more rapid immune reconstitution post transplant.